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Subjects

Abstract

The poorly differentiated hepatocellular carcinoma (HCC) cells are usually characterized by immature hepatic progenitor cell-like properties, such as enhanced self-renewal ability, resistance to chemotherapeutic drugs, and a loss of mature hepatocyte proteins. However, the molecular mechanisms governing this process still remain unclear. In this study, we found the lymphoid enhancer-binding factor-1 (LEF1), a transcriptional factor, was frequently overexpressed in HCCs, which was significantly associated with poor prognosis and tumor cell differentiation. Functional studies have found that LEF1 enhanced cell growth, foci formation, colony formation in soft agar, and tumor formation in nude mice. Different from its canonical roles in the WNT signaling pathway, we found that LEF1 could activate the critical members (e.g., NOTCH1 and NOTCH2) of the NOTCH signaling pathway through directly binding to their promoter regions. Further studies have found that LEF1 could enhance the self-renewal ability, drug resistance, dedifferentiation, and invasion of HCC cells. The oncogenic functions and the effects of LEF1 on cancer stemness could be effectively inhibited by NOTCH inhibitor. Further characterization of LEF1 may lead to the development of novel therapeutic strategies for HCC treatment.

Funding

This work was supported by grants from the Hong Kong Research Grant Council (RGC), including GRF (17143716 and 767313), Collaborative Research Funds (C7038-14G and C7027-14G), Theme-based Research Scheme (T12-704/16-R), and National Natural Science Foundation of China (81772554, 81272416, and 81372583). This work was also supported by the Shenzhen Peacock Team Project (KQTD 2015033117210153). Professor XY Guan is a Sophie YM Chan Professor in Cancer Research.

Author information

Author notes

These authors contributed equally: Shuo Fang, Ming Liu

Affiliations

Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China

Shuo Fang

, Fei-Fei Zhang

, Yun Li

, Qian Yan

, Yu-Zhu Cui

& Xin-Yuan Guan

State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China

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Contributions

S.F. and X.Y.G. initiated and designed the study. S.F. wrote the manuscript with inputs from X.Y.G. and S.F. and M.L. designed the experiments and interpreted the results. S.F. performed all the experiments with assistance from M.L., L.L., F.F.Z., Y.L., Q.Y. and Y.Z.C., HCC clinical samples and the relevant clinical information were provided by Y.H.Z. and Y.F.Y. and X.Y.G. supervised the project.